The current explosive epidemic of Zika virus (ZIKV) in Americas poses a global public health emergency. ZIKV is a member of Flavivirus genus within the Flaviviradae family. Flaviviruses have a positive-strand RNA genome of about 11,000 nucleotides. The flaviviral genome encodes three structural proteins (capsid [C], pre-membrane/membrane [prM/M], and envelope [E]) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The structural proteins form viral particles. The non-structural proteins participate in viral replication, virion assembly, and evasion of the host immune response (Lindenbach et al (2013). Flaviviridae. p. 712-746. In D. M. Knipe and P. M. Howley (ed), Fields virology, 6th., vol. 1. Lippincott William & Wilkins, Philadelphia, Pa.). Like ZIKV, many flaviviruses are significant human pathogens, including yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), and dengue virus (DENV). ZIKV is transmitted by Aedes spp. mosquitoes, which also transmit YFV and DENV, as well as chikungunya virus. In addition, ZIKV may also be transmitted through sex, blood transfusion, organ transplantation, and potentially through urine or saliva (Musso et al., (2014) Euro Surveill 19; Musso et al., (2015) Emerg Infect Dis 21, 359-61). Individuals with compromised immunity could be more susceptible to ZIKV infection and disease development (Shan et al., (2016) ACS Infectious Diseases 2, 170-72).
Experimental systems, including a reverse genetic system of ZIKV, animal models, and mosquito transmission models, are urgently needed to address these key scientific questions. For animal models, A129 (lacking interferon α/β receptors), AG129 (lacking interferon α/β and γ receptors), and Irf3−/− Irf5−/− Irf−/− triple knockout mice were recently reported to be susceptible to ZIKV infection and to develop neurological diseases (Lazear et al., (2016) A mouse model of Zika virus pathogenesis, Cell Host & Microbe; Rossi et al., (2016) Characterization of a Novel Murine Model to Study Zika Virus, Am J Trop Med Hyg; Zmurko et al. (2016) The viral polymerase inhibitor 7-deaza-2′-C-methyladenosine is a potent inhibitor of in vitro Zika virus replication and delays disease progression in a robust mouse infection model. bioRxiv); infection of rhesus macaques with an Asian lineage ZIKV was also reported recently (Dudley et al. (2016). Natural history of Asian lineage Zika virus infection in macaques. bioRxiv). For mosquito infection, one study showed that A. aegypti and A. albopictus mosquitoes are unexpectedly poor vectors for ZIKV, with disseminated infection rates generally <50% following high titer (107 tissue culture infectious dose 50%) oral doses. This suggests the possibility that other mosquito vectors or human-to-human transmission may be contributing to the explosive spread of the virus (Chouin-Carneiro et al., (2016). PLoS Negl Trop Dis 10, e0004543).
The potential association of microcephaly and other congenital abnormalities with Zika virus (ZIKV) infection during pregnancy underlines the critical need for a rapid and accurate diagnosis. Due to the short duration of ZIKV viremia in infected patients, a serologic assay that detects antibody responses to viral infection plays an essential role in diagnosing patient specimens. The current serologic diagnosis of ZIKV infection relies heavily on the labor-intensive Plaque Reduction Neutralization Test (PRNT) that requires more than one-week turnaround time and represents a major bottleneck for patient diagnosis.
There is a need for additional reverse genetic systems for Zika virus, as well as additional methods of detecting and diagnosing viral infections such as Zika virus infection.